Oncotarget

Research Papers:

Altered oncomodules underlie chromatin regulatory factors driver mutations

Joan Frigola _, Ane Iturbide, Nuria Lopez-Bigas, Sandra Peiro and Abel Gonzalez-Perez

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Oncotarget. 2016; 7:30748-30759. https://doi.org/10.18632/oncotarget.8752

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Abstract

Joan Frigola1, Ane Iturbide2, Nuria Lopez-Bigas1,3, Sandra Peiro2, Abel Gonzalez-Perez1

1Research Program on Biomedical Informatics, IMIM Hospital del Mar Medical Research Institute and Universitat Pompeu Fabra, 08003 Barcelona, Catalonia, Spain

2Programa de Recerca en Càncer, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), 08003 Barcelona, Spain

3Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain

Correspondence to:

Abel Gonzalez-Perez, email: [email protected]

Keywords: chromatin regulatory factors, CRFs oncogenic modules, indirect targeted therapeutic strategies, CRFs Oncomodules Discovery, oncogenic modules scoring system

Received: September 29, 2015    Accepted: March 31, 2016    Published: April 15, 2016

ABSTRACT

Chromatin regulatory factors (CRFs), are known to be involved in tumorigenesis in several cancer types. Nevertheless, the molecular mechanisms through which driver alterations of CRFs cause tumorigenesis remain unknown. Here, we developed a CRFs Oncomodules Discovery approach, which mines several sources of cancer genomics and perturbaomics data. The approach prioritizes sets of genes significantly miss-regulated in primary tumors (oncomodules) bearing mutations of driver CRFs. We applied the approach to eleven TCGA tumor cohorts and uncovered oncomodules potentially associated to mutations of five driver CRFs in three cancer types. Our results revealed, for example, the potential involvement of the mTOR pathway in the development of tumors with loss-of-function mutations of MLL2 in head and neck squamous cell carcinomas. The experimental validation that MLL2 loss-of-function increases the sensitivity of cancer cell lines to mTOR inhibition lends further support to the validity of our approach. The potential oncogenic modules detected by our approach may guide experiments proposing ways to indirectly target driver mutations of CRFs.


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